Basic Science and Pathogenesis

Hereditary spastic paraplegia (HSP) is a group of disorders characterized by progressive spasticity and lower limb weakness, with mutations in SPG4/SPAST being the most common cause. Detailed studies and clinical and molecular comparison across different populations are missing. Here we assessed the comprehensive spectrum of neurological features and screened for mutations in SPG4/SPAST gene in patients with HSP.

SPG4/SPAST variants were detected using Direct and Next-Generation Sequencing. The pathogenicity of novel variants was confirmed through familial segregation and in silico analysis. The study involved 726 HSP patients (628 familial, 98 sporadic) recruited from Italy, Brazil, and Japan between 2001 and 2024, with analysis conducted in collaborative centers.

Our study highlights clinical and epidemiological differences between populations, particularly in phenotype, age of onset and disability, expanding the SPG4 clinical spectrum. Genetic analysis found 52 pathogenic SPG4/SPAST mutations in 284 patients, including 20 missense mutations, four of which were novel. Many mutations were population-specific, with a possible founder effect for a recurrent variant in Italy. Notably, 28 HSP-SPG4 patients exhibited a novel form of Alzheimer's disease (AD), confirmed by autopsy in four cases. Additionally, 18 patients with SPG4/SPAST mutations had a thin corpus callosum and intellectual disability.

In this study, we investigated pathogenic SPG4/SPAST variants in an international cohort of HSP patients from three continents. Our results extend the clinical spectrum of HSP-SPG4, discovering a new type complicated by an atypical form of AD. Cautious evaluation of genotype-phenotype relationships proposes insights into patient counseling and future research planning.